Direct Reprogramming of Astrocytes into Functional Serotonergic Neurons

Serotonergic neurons project widely in the central nervous system and regulate a variety of behaviors. Obtaining induced serotonergic neurons (iSNs) iscritical for disease modeling, drug screening and cell therapy. Here, we found that a combination of transcription factors Ascl1, Nkx2.2, Gata2, Foxa2, and Lmx1b could convert postnatal astrocytes into functional serotonergic neurons. We further found that the iSNs expressed serotonergic neuron-specific markers and exhibited similar electrophysiological properties with native serotonergic neurons. More importantly, using an optogenetic stimulation protocol, we demonstrated that the iSNs could form synaptic connections with co-cultured neurons in dishes. Last, after transplanted into the mouse brain, astrocyte-derived iSNs survived, expressed appropriate molecular markers, and matured gradually in vivo. Taken together, our results showed that defined transcription factors were able to convert astrocytes into functional serotonergic neurons andthus provided an alternative option for generate sufficient numbers of a new neuronal subtype for therapeutic therapy.